NRAMP1基因INT4和3’UTR位点多态性与肺结核易感性的研究

目的 探讨人类自然抵抗相关巨噬细胞蛋白1（NRAMP1）基因INT4和3＇UTR位点多态性与中国北方汉族成人肺结核发病的关系.方法 采用1：1配对的病例对照研究设计,用聚合酶链反应-限制性片段长度多态性分析方法检测NRAMP1基因中INT4和3＇UTR两个多态性位点,对与肺结核相关的危险因素进行问卷调查,进行单因素和多因素条件logistic回归分析,同时对基因型与肺结核病变的性质和程度进行研究.结果 对124对研究对象进行了INT4和3＇UTR两个多态性位点的基因分型,3＇UTR TGTG＋/del基因型病例组频率显著高于对照组,粗OR值（95%CI）为2.923（1.557～5.487）.病例组和对照组INT4各基因型频率比较差异均无统计学意义.对17个环境危险因素进行了单因素分析,在多因素分析中调整卡痕、体重指数、人均居住面积、家族史4个因素后,3＇UTR TGTG＋/del基因型仍与肺结核显著相关,调整OR值（95%CI）为2.955（1.369～6.381）.在INT4不同基因型中,病例组和对照组肺结核病变性质差异具有统计学意义（x2=9.634,P＜0.05）.结论 NRAMP1基因3＇UTR位点多态性可能是中国北方汉族成人肺结核的易感因素,而INT4多态性可能与肺结核的病变性质有关系.     

NRAMP1基因D543N和3''''UTR位点多态性与肺结核易感性的研究

目的探讨人类自然抵抗相关巨噬细胞蛋白1(NRAMP1)基因D543N和3'UTR位点多态性与我国北方汉族成人肺结核发病的关系.方法采用11配对的病例对照研究设计,用聚合酶链反应-限制性片段长度多态性分析(PCR-RFLP)的方法检测NRAMP1基因中D543N和3'UTR两个多态性位点,对与肺结核相关的环境因素进行问卷调查的同时对肺结核病变的性质和程度进行了研究,应用SPSS软件进行单因素和多因素条件Logistic回归分析.结果对124对研究对象进行了D543N和3'UTR两个多态性位点的基因分型,D543N G/A、3'UTR TGTG+/del基因型病例组频率显著高于对照组,粗OR值(95%CI)分别为2.625(1.123～6.134)、2.733(1.513～4.938).对17个环境危险因素进行了单因素分析,多因素分析中在调整卡痕、婚姻状况、体质指数、接触史4个因素后,D543N G/A、3'UTR TGTG+/del基因型仍与肺结核显著相关,调整OR值(95%CI)分别为3.151(1.225～8.105)和3.306(1.517～7.201).研究未发现,在不同基因型中,病例和对照组肺结核病变性质差异具有显著性.结论 NRAMP1基因D543N、3'UTR位点多态性可能是我国北方汉族成人肺结核的易感因素.     

东亚人群NRAMP1基因多态性与结核易感性的Meta分析

目的应用Meta分析探讨东亚人群NRAMP1基因3个多态性位点与结核易感性的关系。方法应用主题词和关键词“NRAMP1”、“SLC11A1”、“tuberculosis”和“结核”,检索1995年1月至2005年5月Medline、Ovid及CBMdisc数据库发表的有关文献,并辅以文献追溯的方法。结果结核病组和对照组3’UTR、D543N和INT4位点的多态现象同最常见纯合子基因型频率比值比（OR）的合并OR值分别为1．68（95％CI：1．31～2．16,P〈0．001）;178（95％CI：1,38～2．30,P〈0．001）;1．56（95％CI：0．72～3．35,P=0．26）。Egger线性回归分析提示3’UTR和D543N基因型相关文献没有发表偏倚,INT4基因型相关文献有一定的出版偏倚。结论东亚人群NRAMPl基因3’UTR和D543N多态性位点与结核易感性相关;INT4多态性位点与结核易感性无统计学意义。     

NRAMP1基因和人类对结核分枝杆菌的易感性

NRAMP1基因,又称SLC11A1基因,位于2号染色体长臂35区(2q35),包括15个外显子及内含子4中交替出现的1个外显子,长13 604 bp.NRAMP1的常见多态性基因有D543N、3′UTR、INT4和5′(GT)n等,和结核易感性相关.NRAMP1蛋白由巨噬细胞表达,是一种H+/二价阳离子的反向转运体,对巨噬细胞的功能有多效性.此文对NRAMP1基因及其和MTB的易感相关性的研究结果进行综述.     

NRAMP1和SP110基因多态性与蒙古族结核病易患的关系

目的 探讨NRAMP1基因rs17235409A/G、NRAMP1基因rs17235416TGTG/(-)和Sp110基因rs3948464C/T位点（以下简称NRAMP1rs17235409、NRAMP1rs17235416、SP110rs3948464）基因多态性与蒙古族结核病易患的关系。方法 采用病例-对照研究,收集蒙古族132例结核病患者和108例健康体检者静脉血,应用聚合酶链反应-限制性片段长度多态性(PCR-RFLP)的方法检测3个位点基因分型,运用卡方检验、广义多因子降维法(Generalized Multifactor Dimensionality Reduction,GMDR)分析NRAMP1和Sp110基因多态性及交互作用与结核病易患的关系。 结果 (1)病例组和对照组NRAMP1rs17235409位点GG型,GA型,AA型和NRAMP1rs17235416位点TGTG/TGTG型,TGTG/(-)型,(-)/(-)型基因频率分别为66.67%,30.30%,3.03% vs 86.11%,12.96%,0.93%和60.61%,33.33%,6.06% vs 80.55%,18.52%,0.93%,2个位点基因型与等位基因型在两组的构成均存在差异(〖XC五号.EPS;P〗=12.178,〖XC五号.EPS;P〗=12.462;〖XC五号.EPS;P〗=11.935,〖XC五号.EPS;P〗=13.193,均P＜0.05)。(2)Sp110rs3948464位点CC型和CT型在病例组和对照组的基因频率分别为90.15%,9.85% 和71.30%,28.70%,2组间基因型与等位基因型构成存在差异 (〖XC五号.EPS;P〗=14.105;〖XC五号.EPS;P〗=12.681,均P＜0.05)。(3)GMDR法分析结果显示,NRAMP1rs3948464和NRAMP1rs17235409位点之间存在交互作用(P＜0.05)。结论 NRAMP1rs17235409,NRAMP1rs17235416和Sp110rs3948464位点基因多态性与蒙古族结核病易患有关,NRAMP1rs17235409,NRAMP1rs17235416两位点基因多态性存在交互作用。     

人类NRAMP1基因单核苷酸多态与接尘工人肺结核易感性

目的 探讨人类自然抵抗相关巨噬细胞蛋白1（NRAMP1）基因多态性与接尘工人肺结核易感性的关系.方法 采用1：2病例对照设计,按年龄相差小于5岁,工种、吸烟、饮酒率、总粉尘接触量和矽肺患病同比例匹配,选择61例男性肺结核患者为病例组（矽肺50例、非矽肺11例）,122例男性无肺结核者为对照组（矽肺100例、非矽肺22例）.应用聚合酶链反应-限制性片段长度多态性分析（PCR-RFLP）技术检测NRAMP1 INT4和D543N位点的多态性.结果 NRAMP1 INT4多态位点野生纯合子（G/G）、杂合子（G/C）和突变纯合子（C/C）在病例组的分布频率分别为63.9%、34.4%、1.6%,与对照组比较,差异有统计学意义（P＜0.05）,NRAMP1 INT4 C等位基因携带者患肺结核的危险性升高（OR=2.73,95% CI：1.32～5.64）,D543N位点多态与接尘工人肺结核易感性之间无关联（P＞0.05）.结论 NRAMP1基因第4内含子G＞C单核苷酸可能是接尘工人肺结核的易感因素.     

NRAMP1基因3'UTR多态性与大理地区彝族肺结核易感相关性研究

目的 探讨NRAMP1基因3'UTR位点多态性与大理彝族肺结核病易感相关性及抗结核疗效的联系。方法 采用PCR - RFLP方法检测102例彝族肺结核病人及108例彝族健康人群的NRAMP1基因3'UTR位点的基因型,分析其与彝族人群患肺结核病的易感相关性,且对病人进行抗结核治疗1月后随访及不良反应观察,分析NRAMP1基因多态性与病人抗结核疗效的关系。结果 病例组中NRAMP1基因3'UTR位点AA基因型频率为20.59%,对照组中为5.55%,组间分布差异有统计学意义,χ2 = 14.135,P＜0.001。具有AA基因型的彝族患者肺结核的OR值为6.250,95% CI为2.404～16.247。抗结核治疗后,各基因型患者间胃肠道反应、肝损害及关节损害不良反应的发生率不同,突变型（GA + AA）患者比野生型（GG型）患者更易发生胃肠道反应、肝损伤、关节损害3种不良反应（P＜0.05）。需临床处理的较重不良反应在突变型（GA + AA）患者及野生型（GG型）患者中无统计学差异（P＞0.05）。结论 NRAMP1基因3'UTR位点多态性与大理彝族人群肺结核的易感性相关,可能是大理地区彝族人群肺结核易感的影响因素。A等位基因可能是大理彝族人群肺结核病发病危险因素（OR = 2.069,95% CI = 1.389～3.082 ）。患者抗结核治疗后发生的不良反应情况与NRAMP1基因3'UTR位点多态性存在相关性。     

NRAMP1基因多态性与结核易感性关系的Meta分析

[目的]应用Meta分析探讨NRAMP1基因3'UTR,D543N和INT4多态性位点与结核易感性的关系。[方法]在CNKI、CBM、万方数据资源系统、Medline和Pubmed中,应用关键词"结核"、"基因多态性"(或"遗传多态性")、"等位基因"、"NRAMP1"、"tuberculosis"或"alleles"搜索1980年1月～2007年11月发表的相关中英文文献,最终入选有关文献16篇。应用RevMan4.2软件包分别对16项研究结果进行数据分析。[结果]Meta分析计算得出合并OR值(95%CI)TGTG+-/++为1.50(1.29～1.75),TGTG——/++为0.89(0.59～1.34),GA/GG为1.39(1.20～1.61),AA/GG为1.07(0.69～1.67),GC/GG为1.30(1.09～1.56),CC/GG为1.64(0.90～3.00)。计算3'UTR、D543N和INT4基因的失安全系数为193.87、325.08和157.87,说明分析结果是可靠的。[结论]NRAMP1基因3'UTR(TGTG+-)和D543N(GA)多态性位点均可能是结核的易感因素,尚不能认为INT4多态性位点与结核易感性有关。     

ASAP1和GSTM3基因多态性与肺结核易感性的相关性研究

目的探讨ASAP1及GSTM3基因多态性与肺结核易感性的相关性。方法选择自2017年2月至2018年4月在重庆市长寿区公共卫生服务中心接受治疗的196例肺结核患者为病例组,并以160例体检健康人群作为对照组,静脉取血后提取DNA,采用限制性片段长度多态性方法(polymerase chain reaction-restriction fragment length polymorphisms,PCR-RFLP)法分析ASAP1及GSTM3基因多态性;采用多因素Logistic回归分析讨论肺结核易感性的危险因素。结果病例组的总胆红素为(1.36±0.24)mg/dL,C反应蛋白(C-reactive protein,CRP)为(7.84±1.34)mg/L,白细胞为(9.26±1.38)×10~9/L,均明显高于对照组(P<0.05)。病例组ASAP1基因T2475G位点基因型TT、GT及GG分别为59例、32例及105例,与对照组基因型分布差异有统计学意义(P<0.05)。病例组T2475G位点G等位基因比例为68.6%,显著高于对照(P<0.05)。病例组GSTM3基因A3207C位点基因型AA、AC及CC分别为46例、67例及83例,与对照组基因型分布差异有统计学意义(P<0.05)。病例组A3207C位点C等位基因比例为59.4%,显著高于对照(P<0.05)。多因素Logistic回归分析,发现ASAP1、GSTM3基因多态性是肺结核易感性的危险因素(P<0.05)。结论 ASAP1、GSTM3基因多态性与肺结核易感性的相关性,为肺结核的高危人群筛选及临床治疗提供参考。     

CD209基因3′非翻译区多态性与川崎病的关联性研究

目的探讨CD209基因3′非翻译区(3′UTR)单核苷酸多态性(SNP)与川崎病(KD)及冠状动脉损伤(CAL)的关联性。方法采用Long-PCR方法,对2017年9月至2019年9月在陕西省人民医院儿童病院住院的KD患儿40例(KD组)及同期健康体检儿童40例(对照组)的CD209基因进行全长测序,根据是否合并CAL,KD组又分为CAL组(14例)和非CAL(NCAL)组(26例),分析评价其3′UTR区TagSNPs与儿童KD易感性和CAL发生的遗传关联性。结果KD组的CD209基因rs4804800位点G等位基因和rs11465421位点T等位基因分布频率显著高于对照组(χ~2值分别为3.906、4.103,均P<0.05);rs4804800位点携带G等位基因的基因型较AA基因型发生KD的风险显著增加(OR=2.818,P<0.05),rs11465421位点携带T等位基因的基因型较GG基因型发生KD的风险显著增加(OR=2.714,P<0.05);CAL组各位点基因型及等位基因分布与非CAL组比较均无显著性差异(均P>0.05)。结论CD209基因3′UTR区多态性与儿童KD的易感性相关联,但与CAL的发生无显著关联。     

Association between SLC11A1 polymorphisms and susceptibility to different clinical forms of tuberculosis in the Peruvian population.

Polymorphism in SLC11A1 has been implicated in host susceptibility to tuberculosis. We have studied associations between INT4, D543N, and 3'UTR polymorphisms of SLC11A1 and different clinical forms of TB. Analysis used 507 patients with pulmonary TB, 123 with extra pulmonary TB and 513 controls. INT4 and D543N showed allelic association with pulmonary TB (P=0.02 and 0.03 respectively). INT4-D543N-3'UTR haplotypes showed an association with pulmonary TB (P=0.03). No association of SLC11A1 with miliary TB was observed, and a possible association of D543N to the pleural form (P=0.08) was suggested. These results support association between SLC11A1 and TB, particularly to the common pulmonary form.     

Iron deficiency and NRAMP1 polymorphisms (INT4, D543N and 3'UTR) do not contribute to severity of anaemia in tuberculosis in the Indonesian population

Fe-deficiency anaemia is the most common cause of anaemia in developing countries. In these settings, many chronic infections, including tuberculosis (TB), are highly prevalent. Fe is an essential nutrient for both host and mycobacteria that play a pivotal role in host immunity and mycobacterial growth. A case-control study was performed in a TB-endemic region in Jakarta, Indonesia, among 378 pulmonary TB patients and 436 healthy controls from the same neighbourhood with the same socio-economic status. In a number of these subjects the Fe status could be explored. The distribution of three polymorphisms in the natural resistance-associated macrophage protein gene (NRAMP1) including INT4, D543N and 3'UTR was examined for a possible association with susceptibility to TB. Anaemia (corrected for sex) was present in 63.2 % of active TB compared with 6.8 % of controls, with female patients more often affected. Anaemia was more pronounced in advanced TB as diagnosed by chest radiography. Lower Hb concentrations in TB patients were accompanied by lower plasma Fe concentrations, lower Fe-binding capacity and higher plasma ferritin. After successful TB therapy, Fe parameters improved towards control values and Hb levels normalised, even without Fe supplementation. NRAMP1 gene polymorphisms were not associated with TB susceptibility, TB severity or anaemia. In conclusion, most active TB patients had anaemia, which was probably due to inflammation and not to Fe deficiency since TB treatment without Fe supplementation was sufficient to restore Hb concentration.     

Genetic polymorphisms in alveolar macrophage response-related genes, and risk of silicosis and pulmonary tuberculosis in Chinese iron miners

Alveolar macrophages (AMs) play a prominent role in influencing the development of lung inflammation and injury. The aim of this study is to investigate the roles of AMs response-related genes TNF-alpha, iNOS, and NRAMP1 (SLC11A1) in susceptibility to silicosis and pulmonary tuberculosis (PTB), and to analyze the interaction of dust exposure and genetic susceptibility to silicosis, interactions of TNF-alpha-308 and Natural Resistance-associated Macrophage Protein 1 (NRAMP1) INT4, D543N polymorphisms to PTB. Several epidemiological designs were used: retrospective investigations on dust exposure, case-control studies of 184 silicosis cases and 111 miners occupationally exposed to silica dust, and 1:2 matched case-control studies of 61 PTB cases and 122 PTB-free miners. The miners and controls were recruited from an iron mining operation in Anhui province, China. The polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) technique was applied to detect single nucleotide polymorphisms. Despite the recruitment of high dust exposure among the controls, silicosis patients still had significantly higher dust exposure than controls (242.6 +/- 98.8 vs. 217.6 +/- 100.7 mg a/m(3)). The mutation of iNOS Ser608Leu is associated with protection against silicosis and against severity of silicosis in the miners. There is a 0.47-fold (95% CI: 0.28-0.79) decrease in risk of silicosis for individuals with C/T, T/T genotype compared with the wild-type homozygous (C/C) individuals after adjustment for occupational exposure, smoking, and drinking. The protection effect of the iNOS polymorphism was particularly detected in the > or = 150 mg a/m(3) exposure group (OR: 0.44, 95% CI: 0.22-0.91). However, no interaction of dust exposure with the iNOS polymorphism was observed. Furthermore, the variant NRAMP1 INT4 genotype is significantly associated with PTB in miners. No association of other polymorphisms (NRAMP1 D543N, TNF-alpha-308) and susceptibility to silicosis or PTB in Chinese miners was found. Our data showed a 3.26-fold (95% CI: 1.47-7.23) increased risk of PTB for miners carrying both the NRAMP1 D543N G/G and NRAMP1 INT4 G/C+C/C genotypes. Additionally, in miners with TNF-alpha-308 G/G genotype, the risk of PTB increased 2.38-fold if they carry the NRAMP1 INT4 G/C+C/C genotype (95% CI: 1.14-4.98). In conclusion, the C>T mutation of iNOS Ser608Leu may be an important protective factor to miners. On the other hand, the variant NRAMP1 INT4 may play a role in the development of PTB in Chinese miners. Therefore, the novel information can be used as guideline for further mechanistic investigations and for strengthening specific protection protocols for workers.